Patent GB-643514-A (GB)
Title: Improvements in or relating to methods of producing penicillins
IPC: C07D499/04
Filed: 1947-01-15
Abstract: Novel penicillins of the general formula R-C10H13N2O4S are manufactured by growing a penicillin-producing mould (e.g. a mould of the Penicillium notatum-chrysogenum groups such as strain N.R.R.L. 1976, X1612 or Q-176 or of the Aspergillus group such as strain G147 of A. flavus) in a culture medium which may contain sugars, inorganic salts and desirably one or more indeterminate compositions such as corn steep amino acids or bran (e.g. lactose, corn steep solids, calcium carbonate and water), and which contains, in effective amount to produce a new penicillin but less than about 1 per cent (e.g. 0.01-0.05 per cent w/v), a precursor compound of the formula R-(CH2)n -R1, wherein n is 1, 3 or 5, R1 represents a carboxylic acid group or a functional derivative (e.g. ester, salt or amide) thereof, or a carbinol, carbinamine, aldehyde or acetal group, and R represents an organic radical other than buten-1-yl, butene-2-yl, n-butyl, n-hexyl, phenyl or p-hydroxyphenyl, e.g. an aliphatic radical (saturated or unsaturated and straight or branched chain), a carbocyclic-including radical (which may be attached to the rest of the molecule through an aliphatic group), or a heterocyclic-including radical (e.g. one containing oxygen or sulphur in its nucleus), R and R1 not being the same in any one compound; the radical R may be joined to the rest of the molecule by oxygen or sulphur, or may contain such element as an interrupting atom in an aliphatic chain, and it may contain substituents (e.g. halogen, hydroxy, lower alkyl, lower alkoxy, nitro, aryl, aryloxy, carboxy, carbalkoxy, carbaryloxy, metallo, alkacyl, aracyl, azo, azoxy, hydrazo, cyano, thiocyano, amino, alkylamino, arylamino, thio, thioalkyl, thioaryl, aldehydo, sulphoxy, sulphone or sulphonamido).  When n is 3 or 5, a preliminary degradation of the precursor compound with elimination of 2 or 4 methylene groups apparently takes place, the product obtained being the same as that from the corresponding compound in which n is 1. The pH of the culture medium should be adjusted to about 6-8 prior to the fermentation, which may be of the surface or submerged type and may be carried out at 20-30 DEG  C., especially at 24-26 DEG  C.  The new penicillins may be isolated (preferably in the form of a salt, e.g. the sodium salt) by adsorption and extraction methods, and, if desired, further purified by such methods as partition chromatography and recrystallization, of which details are given.  Examples describe the use of the following precursor substances: N-(2-hydroxyethyl)-p-methoxyphenylacetamide, p-methoxyphenylacetic acid and its ethyl ester and p-methoxyphenethylamine (all of which yield a product in which R = p-methoxyphenyl); N-(2-hydroxyethyl) - a - thienylacetamide (R = a -thienyl); N-p-chlorophenylacetylvaline and p-chlorophenylacetic acid (R = p-chlorophenyl); N-(2-hydroxyethyl)-p-methylphenylacetamide and p-methylphenethylamine R = p-tolyl); N-p-nitrophenylacetyl-valine and -isoleucine (R = p-nitrophenyl); N-(2-hydroxyethyl)-o-, m- and p-fluorophenylacetamide and p-fluorophenethylamine (R = o-, m- or p-fluorophenyl); N-g -(p-bromophenyl) - butyrylvaline and b  - p - bromophenethanol (R = p - bromophenyl); N - (2-hydroxyethyl) - phenoxyacetamide (R = phenoxy); N - (2 - hydroxyethyl) - p - iodophenylacetamide (R = p - iodophenyl); N - p - tolylmercaptoacetylvaline (R = p - tolylmercapto); N - (2-hydroxyethyl) - vinylacetamide (R = vinyl); N-cyclohexylacetylvaline (R = cyclohexyl.  A table shows the products obtained from N-(2-hydroxyethyl) - homopiperonylamide (R = 3 : 4-methylenedioxyphenyl), N-(2-hydroxyethyl)-a -furylacetamide (R = a - furyl), N - (21 - hydroxyethyl) - 3 : 4-dichlorophenylacetamide (R = 3 : 4-dichlorophenyl), N-(2-hydroxyethyl)-o-bromophenylacetamide (R = o - bromophenyl), N - (21-hydroxyethyl) - 5 : 6 : 7 : 8 - tetrahydro - 2 - naphthylacetamide (R = ar - tetrahydro - b  - naphthyl) and N - (21 - hydroxyethyl) - 6 - quinolylacetamide (R = 6-quinolyl).  It is stated that R may also be D 8-nonenyl, allyl, tert.-butyl, allyloxy, ethylmercapto, cyclopentyl, cyclohexenyl, benzylmercapto, styryl, a  : a -dimethylbenzyl, 4 : 5-benzofuryl, a -(2-thienyl)-ethyl, 2-furylmethylmercapto, 6 - quinolyloxy, p chloromethyl, hydroxymethyl, g -chloroallylmercapto, a  : a -dimethyl - p - nitrobenzyl, 5 - bromo - 2 - thienyl, m-bromophenylmercapto or 4-methyl-6-quinolyloxy, whilst additional precursor substances specified are sodium b -naphthylacetate, N-(2-thienyl) - acetylvaline, b  - p - tolylethanol, N - (2-hydroxyethyl)-g -(p-bromophenyl)-butyramide, b -chloropropionaldehyde diethyl acetal, ethyl vinylacetate, p-bromophenylacetic acid and g -(p-bromophenyl)-butyric acid.  The preparation of many of the precursor substances is described, the reactions falling into the following general classes:-  N-(2-Hydroxyethyl)-amides of substituted acetic acids are prepared by heating the methyl or ethyl ester of the appropriate acid with ethanolamine, or (in the case of the vinylacetic amide) by reacting the acid chloride with ethanolamine in chloroform.  N-(Substituted acetyl) derivatives of valine and isoleucine are prepared by reacting the appropriate substituted acetyl chloride with valine or isoleucine in the presence of caustic soda solution.  Certain of the acids corresponding to the above starting materials are prepared as follows:-  p-Tolylmercaptoacetic acid by heating p-thiocresol with chloracetic acid in the presence of caustic soda solution.  3 : 4-Dichlorophenylacetic acid by brominating 3 : 4-dichlorotoluene, treating the resulting 3 : 4-dichlorobenzyl bromide with potassium cyanide in aqueous ethanol, and hydrolysing the resulting 3 : 4-dichlorophenylacetonitrile.  5 : 6 : 7 : 8-Tetrahydro-2-naphthylacetic acid by heating 2-aceto-5 : 6 : 7 : 8-tetrahydronaphthalene with sulphur and morpholine. 6-Quinolylacetic acid by heating p-aminophenylacetic acid with glycerol, ferrous sulphate, nitrobenzene and concentrated sulphuric acid.  The Specification as open to inspection under Sect. 91 comprises also the use of precursor compounds of the general formula above in which the radical R may be interrupted by, or attached to the rest of the molecule by, a nitrogen atom, and may contain as additional substituents carboxamido or acylamino groups.  It gives a long list of additional radicals which may be represented by R, and a lengthy second table of products and corresponding precursors, and describes the preparation of many of these precursors by the methods outlined above and of certain of the corresponding acids by methods analogous to those for 5 : 6 : 7 : 8-tetrahydro-2-naphthylacetic acid, p-tolylmercaptoacetic acid and 3 : 4-dichlorophenylacetic acid above.  Other precursors and starting materials therefore are prepared as follows: b  : b -dimethyl-g -pentinoic acid by condensing 1 : 1-dimethyl-1-chloropropine-2 with sodiomalonic ester, and hydrolysing and decarboxylating the resulting diethyl 2-(a  :a -dimethyl-b -propine)-malonate; N-allyl-b  - chloropropionamide and N - allylstyrylacetamide by condensing allylamine with b -chloropropionyl and styrylacetyl chlorides respectively; N - (21 - hydroxyethyl) - 3 : 5 - diacetomercuri-4-hydroxyphenylacetamide by treating N - (21 - hydroxyethyl) - 4 - hydroxyphenylacetamide with acetic acid and mercuric acetate in aqueous ethanol; m-trifluoromethylacetophenone by converting m-trifluoromethylacetophenone by converting m-trifluoromethylaniline by the Sandmeyer reaction to m-trifluoromethylbenzonitrile and treating this with methylmagnesium iodide followed by hydrolysis; 6-fluoro- and 6-bromo-2-methylnaphthalene by the Sandmeyer reaction from 2-methyl-6-aminonaphthalene; m-trifluoromethylphenoxyacetic acid by condensing m-trifluorophenol with chloracetic acid in the presence of caustic soda solution; 2-cyclopentene-1-acetic acid by hydrolysis and decarboxylation of diethyl 2-cyclopentenylmalonate; p-carbethoxyhydroxyphenylacetic acid by treating p-hydroxyphenylonetic acid with ethyl chlorocarbonate in the presence of caustic soda solution; p - methylmercapto- and p - phenylmercapto-acetophenone by treating thioanisol and diphenyl sulphide respectively with acetyl chloride in carbon disulphide in the presence of anhydrous aluminium chloride; ethyl p-benzyloxy- and p-allyloxy-phenylacetate by treating ethyl p-hydroxyphenylacetate with benzyl chloride and allyl bromide respectively in absolute ethanol in the presence of sodium methoxide; 2 : 4-dichlorophenylacetic acid by treating 2 : 4-dichlorobenzyl chloride with potassium cyanide and hydrolysing the resulting nitrile; 3 : 4-dibromotoluene by the Sandmeyer reaction from 3-bromo-4-aminotoluene.  This subject-matter does not appear in the Specification as accepted.